Although triglycerides (also known as “triacylglycerides”) are essential for normal physiology, excess triglyceride accumulation results in obesity and, particularly when it occurs in nonadipose tissues, is associated with insulin resistance. Obesity increases the risk of many common and serious conditions, including coronary heart disease, hypertension, dyslipidemia, atherosclerosis, type-II diabetes, stroke, osteoarthritis, restrictive pulmonary disease, sleep apnoea, certain types of cancers and inflammatory disorders. The standard treatment for obesity is calorific restriction and increase of physical exercise. However, such approaches are rarely successful and pharmaceutical treatments are required to correct these metabolic disorders.
A potential therapy for these conditions therefore involves inhibiting triglyceride synthesis.
Diacylglycerol acyl-transference (DGAT) is an enzyme that catalyzes the last step in triacylglycerol biosynthesis. DGAT catalyzes the coupling of a 1,2-diacylglycerol with a fatty acyl-CoA resulting in Coenzyme A and triacylglycerol. Two enzymes that display DGAT activity have been identified: DGAT1 (acyl coA-diacylglycerol acyl transferase 1) [Cases et al., Proc. Natl. Acad. Sci. 1998, 95:13018-13023] and DGAT2 (acyl coA-diacylglycerol acyl transferase 2) [Cases et al., J. Biol. Chem. 2001, 276:38870-38876].
DGAT1 and DGAT2 do not share significant protein sequence homology. Importantly, however, DGAT1 knockout mice are protected from high fat diet-induced weight gain and insulin resistance [Smith et al., Nature Genetics 2000, 25:87-90]. The phenotype of the DGAT1 knockout mice suggests that DGAT1 inhibitors would be useful for the treatment of obesity and obesity-associated complications [Smith et al., Nature Genetics 2000, 25:87-90].
There is therefore a need for compounds which inhibit the activity of DGAT1.